Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial
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Abstract
Objective
To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19).
Design
Multicentre, open label, randomised controlled trial.
Setting
16 government designated covid-19 treatment centres in China, 11 to 29 February 2020.
Participants
150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone).
Interventions
Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively).
Main outcome measure
Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone.
Results
Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events.
Conclusions
Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.
Trial registration
ChiCTR2000029868.
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SciScore for 10.1101/2020.04.10.20060558: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Trial oversight: The study was designed and initiated by the principal investigators after the protocol was approved by the institutional review board in Ruijin Hospital on February 6, 2020.
Consent: Written informed consent was obtained from all patients.Randomization Trial design, Randomization, and procedures: This study was a multicenter, randomized, parallel, open–label, trial of HCQ in hospitalized patients with COVID–19. Blinding not detected. Power Analysis With the assumption that time to conversion follows an exponential distribution, the median time to conversion in HCQ can be reduced from 10 days to 7 days, therefore, a total of 248 events would … SciScore for 10.1101/2020.04.10.20060558: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Trial oversight: The study was designed and initiated by the principal investigators after the protocol was approved by the institutional review board in Ruijin Hospital on February 6, 2020.
Consent: Written informed consent was obtained from all patients.Randomization Trial design, Randomization, and procedures: This study was a multicenter, randomized, parallel, open–label, trial of HCQ in hospitalized patients with COVID–19. Blinding not detected. Power Analysis With the assumption that time to conversion follows an exponential distribution, the median time to conversion in HCQ can be reduced from 10 days to 7 days, therefore, a total of 248 events would provide a power of 80% to detect Hazards Ratio (HR)=0.7 (SOC vs. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Strengths and limitations of this study: This study provides the first and timely evidence regarding benefit–risk of HCQ derived from a multi–center randomized controlled trial, which was initiated during the most challenging time of the COVID–19 outbreak in China. Under such a situation, our study does have several limitations. First, the design of open–label, as opposed to double–blind design, introduces biased investigator–determined assessments and unbalanced dosage adjustment. Urgent production of placebos mimicking HCQ and the management of a multi–center placebo–controlled trial remains challenging during the pandemic. Second, the use of sequential envelopes is inferior to the interactive web response management system for randomization. Third, the conduction of our trial in the setting of hospitalized patients precludes us from enrolling patients at the early disease stage. In addition, we cannot provide evidence on the utility of HCQ regarding disease progression or regression because 148 out of 150 (99%) patients in our trial are with mild to moderate disease. Fourth, the results on our main pre–specified outcomes are not entirely conclusive based on underpowered sample size due to the lack of enough eligible patients to enroll. The recruitment of eligible patients was unexpectedly difficult with almost hundreds of clinical trials launched in the same period in response to the urgent call for the exploration of effective treatment against COVID–19 by the national he...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.04.10.20060558: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement METHODS Trial oversight The study was designed and initiated by the principal investigators after the protocol was approved by the institutional review board in Ruijin Hospital on February 6 , 2020 . Randomization What this study adds —In this randomized clinical trial of patients mainly with persistent mild to moderate COVID–19 , exposure to hydroxychloroquine led to a similar probability of virus elimination comparing to the current standard–of–care. Blinding not detected. Power Analysis With the assumption that time to conversion follows an exponential distribution , the median time to conversion in HCQ can be reduced from 10 days to 7 days , therefore … SciScore for 10.1101/2020.04.10.20060558: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement METHODS Trial oversight The study was designed and initiated by the principal investigators after the protocol was approved by the institutional review board in Ruijin Hospital on February 6 , 2020 . Randomization What this study adds —In this randomized clinical trial of patients mainly with persistent mild to moderate COVID–19 , exposure to hydroxychloroquine led to a similar probability of virus elimination comparing to the current standard–of–care. Blinding not detected. Power Analysis With the assumption that time to conversion follows an exponential distribution , the median time to conversion in HCQ can be reduced from 10 days to 7 days , therefore , a total of 248 events would provide a power of 80 % to detect Hazards Ratio ( HR)=0.7 ( SOC vs. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Funding , competing interests , data sharing This work was supported by the Emergent Projects of National Science and Technology ( 2020YFC0844500) , National Natural Science Foundation of China ( 81970020 , 81770025) , National Key Research and Development Program of China ( 2016YFC0901104) , Shanghai Municipal Key Clinical Specialty ( shslczdzk02202 , shslczdzk01103) , National Innovative Research Team of High–level Local Universities in Shanghai , Shanghai Key Discipline for Respiratory Diseases ( 2017ZZ02014) , National Major Scientific and Technological Special Project for Significant New Drugs Development ( 2017ZX09304007) , Key Projects in the National Science and Technology Pillar Program during the Thirteenth Five–year Plan Period ( 2018ZX09206005–004 , 2017ZX10202202–005–004 , 2017ZX10203201–008) . Technology Pillar Programsuggested: (Helmholtz Center Munich, SCR_011282)Results from Barzooka: We also found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.
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